Highlights from AACR 2015: The Emerging Potential of Immunotherapeutic Approaches in Non-Small Cell Lung Cancer

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1 Transcript Details This is a transcript of a continuing medical education (CME) activity accessible on the ReachMD network. Additional media formats for the activity and full activity details (including sponsor and supporter, disclosures, and instructions for claiming credit) are available by visiting: Released: 05/04/2015 Valid until: 05/04/2016 Time needed to complete: 15 minutes ReachMD info@reachmd.com (866) Highlights from AACR 2015: The Emerging Potential of Immunotherapeutic Approaches in Non-Small Cell Lung Cancer NARRATOR OPENING: Welcome to Project Oncology on ReachMD. This is the Prova Education activity: Immunotherapy in Non-Small Cell Lung Cancer: Conference Coverage highlights from the American Association for Cancer Research (AACR) Host Dr. Matt Birnholz, welcomes Dr. Evan Alley, Clinical Associate Professor, Co-Director, Penn Mesothelioma and Pleural Program, Chief, Hem/Onc Division at Penn Presbyterian Abramson Cancer Center in Philadelphia, Pennsylvania. Dr. Alley has nothing to disclose ReachMD Page 1 of 8

2 Dr. Matt Birnholz has nothing to disclose. This CME activity is supported by an independent educational grant from Merck. Upon completion of this CME activity describing key immunotherapy findings from the 2015 American Association for Cancer Research Annual Meeting, learners with an interest in non-small cell lung cancer (NSCLC) will be better able to: 1. Understand the rationale for using immunotherapeutic agents in the treatment of NSCLC 2. Appreciate the potential impact of anti-ctla-4 and anti-pd-1 and PD-L1 antibodies in the management of NSCLC 3. Assess the role biomarkers may have in individualizing the treatment of patients with NSCLC 4. Anticipate and possibly prevent immune-related adverse events in patients with NSCLC HOST INTRODUCTION: The American Association for Cancer Research (AACR) held its 2015 annual congress to highlight and present new data on some of the latest and most exciting discoveries in cancer research. This year s meeting theme Bringing Cancer Discoveries to Patients underscores the vital and inextricable link between discovery and treatment, and reinforces that research underpins the progress we are making toward cancer cures. Joining us today is Dr. Evan Alley, who attended AACR 2015 and will give an update on some of the exciting data presented on the emerging potential of immunotherapeutic approaches in non-small cell lung cancer. Dr. Matt Birnholz: Dr. Alley, welcome to the program. Dr. Evan Alley: Thank you for having me. I appreciate it. Immunotherapy was a major topic at AACR this year. What was presented that piqued your interest most? Dr. Alley: 2018 ReachMD Page 2 of 8

3 The theme of AACR in 2015 was The Genome and Beyond, and the immunotherapy in that regard and the way it interacts with the genome was actually a major topic, as you said. In the opening sessions of the meeting, there was an award lecture by Dr. James Allison. He received the 18th Annual Pezcoller Foundation Award. And he presented a lecture describing his seminal work in the field of immunotherapy. The lecture described the discovery of the T-cell antigen receptor and how it's used by T-cells to recognize and bind antigens, as well as the discovery of the secondary signals that are required, such as binding of B7 molecules on antigen-presenting cells to CD28 and this resulting in second signal for activation. But really what founded the field of immunotherapy, at least recently, was the discovery of some molecule, CTLA-4, which has been shown to inhibit T-cell function and in a normal setting to protect the normal tissue from attack. It also was shown that CTLA-4 expression on T-cells protects cancer cells from attack as well. And so this protein was dubbed an immune checkpoint. This work that Dr. Allison presented really was what led to the development of a whole new field of immunotherapy, and this was development of CTLA-4 antibodies which were shown to inhibit the immune checkpoint and induce responses against tumors. The first clinical development of this treatment was a CTLA-4 antibody called ipilimumab, and this was the first immune checkpoint inhibitor that was approved for treatment of metastatic melanoma. His work ushered in a whole new era of immuno-oncology, and there's been now multiple inhibitors and activators of T-cell function that have been identified. The next major development that was described was the discovery of PD-1, which is another immune checkpoint protein, as well as its ligands PDL-1 and PDL-2. These are known to play an important role in tumor immunity. There are multiple antibodies that are now in development targeting the PD-1 pathway. These are both PD-1 antibodies as well as PDL-1 antibodies. And currently, there are 2 PD- 1 antibodies that have been approved for treatment of advanced melanoma. That was nivolumab and pembrolizumab. So, in the opening plenary session of AACR, the results of the KEYNOTE-006 study were presented by Dr. Antoni Ribas. This was a randomized Phase III trial evaluating pembrolizumab versus ipilimumab, the CTLA-4 antibody, in advanced melanoma, and these were patients who had not had any prior immune checkpoint therapy. The results of this study were actually simultaneously published in the New England Journal of Medicine. This study was important in that it demonstrated for the first time superiority of pembrolizumab, the PD-1 antibody, over ipilimumab. The study showed that treatment with pembrolizumab reduced the risk of death by 31-37%. In terms of 6-month progression-free survival, there was a 1.8-fold improvement in favoring pembrolizumab. And this was also seen in overall response rate where the improvement was 2.8-fold, again favoring pembrolizumab. So this was 2018 ReachMD Page 3 of 8

4 in melanoma. And now the role of PD-1 antibody in non-small-cell lung cancer is also being evaluated in multiple trials. As you may know, nivolumab, the PD-1 antibody, was just recently approved by the FDA for treatment of advanced squamous cell carcinoma of the lung, and this was based on data from the CheckMate-017 study. This was a randomized Phase III trial that was conducted in 272 patients with advanced or metastatic squamous cell lung cancer, and the patients were randomly assigned to treatment with either nivolumab or standard of care, which was docetaxel. This trial was actually stopped early. When the primary endpoint of overall survival was met, the trial showed that patients who received nivolumab lived about 3.2 months longer than those who received the standard of care, docetaxel; and in terms of the data, the overall survival for the nivolumab arm was 9.2 months compared to 6 months for docetaxel. This was a reduction in the risk of death. The hazard ratio was This was a really important study. It's the first time the immunotherapy has shown a survival benefit in lung cancer. So there's been a lot of excitement about this data, and this is sort of the fruition of several years of study. On the day prior to the AACR meeting, the CheckMate-057 study, which is another trial evaluating nivolumab versus standard of care, docetaxel, but this time in nonsquamous lung cancer, this study was also stopped early because of a survival benefit. This was a randomized Phase III study evaluating nivolumab. The Independent Data Monitoring Committee concluded that the study had met its endpoint, which means that it demonstrated a superior overall survival in patients receiving nivolumab compared to the control arm of docetaxel. The data for the results have not been released yet, but undoubtedly, these results will lead to the approval of nivolumab in nonsquamous lung cancer as well. What at AACR has excited you most about the future potential of modulating the checkpoint pathway in non-small cell lung cancer? Dr. Alley: So on the opening day of AACR, the results of the KEYNOTE-001 study were presented by Dr. Edward Garon. Again, these study results were simultaneously published in the New England Journal of Medicine. So KEYNOTE-001 was a Phase IB study, which is evaluating pembrolizumab in non-smallcell lung cancer in a sort of complicated study with a series of expansion cohorts that included both PDL-1 positive and PDL-1 negative patients. They were also patients who were either previously treated or treatment naïve. So over the series of cohorts, there were nonrandomized cohorts of PDL-1 positive and PDL-1 negative. There were also randomized cohorts in PDL-1 positive patients that were 2018 ReachMD Page 4 of 8

5 treated at different dose levels. While being a complicated study, what the overall result did show that on the whole study population the overall response rate was about 19.4% and the median duration of response was 12.5 months, and this was important. What I think we should take home from this study was that there were no clear differences with regard to patients who had had prior therapy, no clear differences regarding the different histologies, squamous versus nonsquamous, and there were no real differences seen between the different dose levels. The median overall survival for the patient population was 12 months, and this included 9.3 months for the previously treated patients, and 16.2 months for those who were treatment naïve; although, this difference really was not statistically significant. The important things, again, from the trial were that there was a relatively low rate of adverse events and there were no new safety signals. Another part of this study, and maybe the more important part of the study, was the role of PDL-1 expression in terms of response to pembrolizumab. In the patients who had a high expression of PDL- 1 those were that 50% or higher on the tumor cells showed an overall response rate of 45%. When you look at those tumor types that expressed a lower level of PDL-1, 1-49%, the overall response rate was lower at 16.5%. And those tumors that were PDL-1 negative had an overall response rate of 10.7%. So it clearly demonstrated that higher levels of PDL-1 expression correlate with overall response. That response also seemed to correlate with overall survival. In the patients who had low expression, 49% or less, the median overall survival was 8.8 months. Patients with high PDL-1 expression, again greater than 50%, the median overall survival for the study had not yet been reached. So while high PDL expression in non-small-cell lung cancer predicts a better response to pembrolizumab, even the PDL-1 negative patients do have some response and clinical benefit. The current FDA approval for nivolumab in squamous cell carcinoma does not require PDL-1 testing. And I suspect that PDL-1 expression will not be required for pembrolizumab as well, if and when it is approved, for treatment of non-small-cell lung cancer. Dr. Birnholz Mid-Tag: If you are just tuning in, you are listening to CME on ReachMD. I m your host Dr. Matt Birnholz, and today we re talking with Dr. Evan W. Alley, from Penn Presbyterian Abramson Cancer Center in Philadelphia, where he serves as co-director of the Penn Mesothelioma and Pleural Program. Dr. Alley is sharing with us some highlights from AACR 2015, which he recently attended, and is discussing the Emerging Potential of Immunotherapeutic Approaches in Non-Small Cell Lung Cancer. So Dr. Alley, getting back to our discussion, what about the use of biomarkers to identify a specific patient to a particular immunotherapy agent or regimen? Anything new to report? 2018 ReachMD Page 5 of 8

6 Dr. Alley: Well, building on the data that was presented in non-small-cell lung cancer from the KEYNOTE-001 study, other trials are using PDL-1 expression as a predictor of response to PD-1 antibody therapy. There was a poster at AACR that described the use of a gene expression profile for PDL-1 across multiple tumor types, and this was used to predict those subtypes that were most likely to respond to PD-1 antibody therapy. In this study they were using a custom gene chip that looked at 16,000 primary tumors and more than 3,000 metastatic tumors. The tumors were ranked by a fraction of expression of PDL-1 that exceeded 75%. And as expected, melanoma, non-small-cell lung cancer, those were among the highest of the PDL-1 expressing tumors, and activity of checkpoint inhibitor therapy in these tumors have already been demonstrated. Other high-expressing tumor types were head and neck cancer, triple negative breast cancer and bladder cancer, all of which are of particular clinical interest. Low expression was seen in pancreatic adenocarcinomas, prostate cancer and colon cancer, again, all of which have demonstrated little response to PD-1 antibody therapy in early studies. So this approach to gene expression profiling may help identify tumors and subtypes of tumors that may be more likely to respond to immune checkpoint inhibitor therapy. We know from use of checkpoint inhibitors in melanoma that we should expect a range of side effects. What have we seen so far in non-small cell lung cancer? Anything new to report? Dr. Alley: The results of the KEYNOTE-001 study included an in-depth analysis of toxicities. I think what the take-home message from that study was is that immune checkpoint antibodies do have significant toxicities or can have significant toxicities, but overall, the newer PD-1 antibodies appear to be better tolerated than historically what was seen with the initial CTLA-4 antibodies. There appear to be lower rates of autoimmune toxicity seen. In the non-small lung cancer study, the most common toxicity was fatigue, pruritus, rash. There were immune-mediated events that were also seen, but again relatively uncommon. The most common one was hypothyroidism or hyperthyroid, seen in less than 10% of patients. Pneumonitis, which is a serious toxicity, especially in the lung cancer population, was seen at less than 4%, and other autoimmune toxicities such as colitis or hypophysitis were also less than 1%. So in this trial it seemed that these agents were relatively well tolerated, had a predictable and manageable side effect profile, and there were no new safety concerns that were found in the lung cancer studies. Lastly, a 2014 publication by Dolan and Gupta published in Cancer Control as well as others 2018 ReachMD Page 6 of 8

7 have suggested that immunotherapeutic agents focused on the checkpoint pathway have shown activity in a number of cancers other than melanoma and non-small cell lung cancer, such as colorectal, kidney, bladder, and head and neck cancers to name a few. Could you comment on that perspective and offer any information at AACR that further supports that perspective? So, the activity of checkpoint inhibitors has been demonstrated across multiple tumor types including, as you said, melanoma and non-small-cell lung cancer, also head and neck cancers, urothelial cancers, triple-negative breast cancer. Most recently there was a very nice paper in the New England Journal of Medicine describing a robust response in relapsed classical Hodgkin s lymphoma. This was in response to pembrolizumab. So at AACR this year there was data from the KEYNOTE-028 study, that I actually presented, regarding activity of pembrolizumab in pleural mesothelioma. So just as a background, the KEYNOTE- 028 study is a multicenter trial evaluating pembrolizumab in PDL-1 positive tumors. This is actually looking at 20 different tumor types, and the mesothelioma cohort was what was presented at the meeting. So this study enrolled 25 patients with malignant pleural mesothelioma that had tumors that tested for PDL-1 positivity expressed in at least 1%. In this study population, the overall response rate with treatment of pembrolizumab was 28% with a disease control rate of 76%, so that includes patients who had stable disease. This is, I think, clinically important. If we think about this patient population that had been previously treated, the response rates historically are 10% or less, so this seemed to be a significant signal of efficacy in this patient population. At the time of the data cutoff in January 2015, 40% of the patients continued on therapy for more than 24 weeks. So this is an important signal showing that pembrolizumab and these other immune checkpoint inhibitors have activity across a broad range of tumors. Data analysis for the KEYNOTE-028 study is ongoing, and additional cohorts, different tumors types from this study will be presented at the upcoming meetings. So immune checkpoint inhibitor therapy appears to be applicable to really a wide variety of tumors, and PDL-1 expression seems to correlate with that response. And the most responsive tumors to date, those that have the highest expression, are more likely to respond. However, some common tumor types such as colorectal cancer, pancreatic cancer, prostate cancer, really have not shown much activity with regard to immune checkpoint inhibitors. So there's clearly additional studies, additional research that needs to be done to determine why immune checkpoint inhibitor therapy is less effective for these tumor types and if there's a way to induce an immune response, somehow improve T-cell trafficking or even up regulate PDL-1 expression in the tumor microenvironment? There were several presentations at AACR this year discussing the role of tumor neoantigens in 2018 ReachMD Page 7 of 8

8 relation to mutational burden of the tumor as predictors of response to immunotherapy. There appears to be a direct correlation between mutational burden in the tumor with the reduction of tumor neoantigens and the potential for T-cell response. Studies with personalized vaccines using tumor neoantigens are now underway, and perhaps combination therapy with immune checkpoint inhibitors will be a next step in personalized immunotherapy for lung cancer as well as other malignancies. Well with that I want to very much thank our faculty, Dr. Evan Alley, for giving us an excellent update on some of the exciting data recently presented at AACR 2015 on the emerging potential of immunotherapeutic approaches in non-small cell lung cancer. Again, Dr. Alley, thank you so much for your time and insights. Dr. Alley: My pleasure, thank you! NARRATOR CLOSE: This segment of Project Oncology on ReachMD is brought to you by Prova Education. To receive your free CME credit or to download this segment, go to ReachMD-dot-com-forward slash-projectoncology ReachMD Page 8 of 8